Abstract
Aim:
To examine the insulin sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative YY20 in insulin-sensitive cell lines.
Methods:
The peroxisome proliferator-activated receptor γ (PPARγ) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein. The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line.
Results:
YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene expression of PPARγ2, as well as the protein expression of insulin receptor sub-strate-1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPARγ inhibitor SR-202. Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations.
Conclusion:
YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulin-dependent manner. It may improve the insulin resistance associated with type 2 diabetes.
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Porte, D Jr, Schwartz, MW . Diabetes complications: why is glucose potentially toxic? Science 1996; 272: 699–700.
Seidell JC . Obesity, insulin resistance and diabetes — a worldwide epidemic. Br J Nutr 2000; 83 suppl 1: S5–8.
Boyle PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, et al. Effects of pioglitazone and rosiglitazone on blood lipid level and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002; 24: 378–96.
Vasudevan AR, Balasubramanyam A . Thiazolidinediones: a review of their mechanisms of insulin sensitization, therapeutic potential, clinical efficacy, and tolerability. Diabetes Technol Ther 2004; 6: 850–63.
Willson TM, Brown PJ, Sternbach DD, Henke BR . The PPARs: from orphan receptors to drug discovery. J Med Chem 2000; 43: 527–50.
Tontonoz P, Hu E, Spiegelman BM . Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994; 79: 1147–56.
Kletzien RF, Clarke SD, Ulrich RG . Enhancement of adipocyte differentiation by an insulin sensitizing agent. Mol Pharmacol 1992; 41: 393–8.
Choi Y, Kawazoe Y, Murakami K, Misawa H, Uesugi M . Identification of bioactive molecules by adipogenesis profiling of organic compounds. J Biol Chem 2003; 278: 7320–4.
Kitajima H, Nakamura M, Goto N . Hybridization of non-sulfonylurea insulin secretagogue and thiazolidinedione-derived insulin sensitizer. Bioorg Med Chem Lett 2000; 10: 2453–6.
Brooks DA, Etgen GJ, Rito CJ, Shuker AJ, Dominianni SJ, Warshawsky AM, et al. Design and synthesis of 2-methyl-2-[4–(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic acids: a new class of dual PPARalpha/gamma agonists. J Med Chem 2001; 44: 2061–4.
Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W . Quantition of adipose conversion and triglycerides by staining intracytoplasmic lipids with oil red O. Histochemistry 1992; 97: 493–6.
Yin J, Hu R, Chen M, Tang J, Li F, Yang Y, et al. Effects of berberine on glucose metabolism in vitro. Metabolism 2002; 51: 1439–43.
Lott JA, Turner K . Evaluation of Trinder's glucose oxidase method for measuring glucose in serum and urine. Clin Chem 1975; 21: 1754–60.
Hansen MB, Nielsen SE, Berg K . Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 1989; 119: 203–10.
Camp HS, Li O, Wise SC . Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539–47.
Vazquez M, Silvestre JS, Prous JR . Experimental approaches to study PPARγ agonists as antidiabetic drugs. Methods Find Exp Clin Pharmacol 2002; 24: 515–23.
Lowell BB . PPARγ: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999; 99: 230–53.
Okuno A, Tamemoto H, Tobe K . Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese zucker rats. J Clin Invest 1998; 101: 1354–61.
Ntambi JM, Young-Cheul K . Adipocyte differentiation and gene expression. J Nutr 2000; 130: S3122–26.
Wu Z, Xie Y, Morrison RF, Bucher NL, Farmer SR . PPARγ induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPα during the conversion of 3T3 fibroblasts into adipocytes. J Clin Invest 1998; 101: 22–32.
White MF, Kahn CR . The insulin signaling system. J Biol Chem 1994; 269: 1–4.
Matsuzawa Y . The metabolic syndrome and adipocytokines. FEBS Lett 2006; 580: 2917–21.
Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A . Peroxisome proliferator-activated receptor gene expression in human tissues. J Clin Invest 1997; 99: 2416–22.
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Project supported by the Natural Science Foundation of Zhejiang Province (No Y206234).
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Wu, Hs., Yu, Jh., Li, Yy. et al. Insulin-sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative in vitro. Acta Pharmacol Sin 28, 417–422 (2007). https://doi.org/10.1111/j.1745-7254.2007.00506.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00506.x